This application is a 371 of PCT/EP98/06864 filed Oct. 29, 1998.
The present invention relates to a complex between a water soluble drug and carrageenan in powder form characterised in that this powder has a specific granulometry, a process for preparing this complex and controlled release pharmaceutical composition containing said complex.
One of the simplest and cheapest methods to obtain the prolonged release of drugs is the use of tablets containing the drug and one or more polymers quite often able to gelify. Especially in the case of very soluble drugs, however, the release rate is higher at the beginning of the dissolution and decreases with the increase in diffusional pathway. This can result in strong variations of plasma levels especially in the case of drugs administered at high dosages.
Solid oral dosage forms based on ion exchangers are described in the literature. Ionic exchange resins and hydrophilic polymers with ionisable groups have been used. Most of the commonly used drugs, being basic in nature, can interact with polymer acidic groups (carboxylic or sulfonic groups). The sulfonic polymers, being stronger acids, are likely to interact with the drug independently of the pH of the medium. In any case, the ionic interaction between the drug and the polymer gives as a result a change of the release profiles of the drug. In particular, with some drugs a precipitation of the complex may occur.
Drug-carrageenan complexes have been proposed for the sustained release in parenteral administration (intramuscular) (H. D. Graham et al, J. Pharm. Sci, 52,1963,193-198).
Moreover, complexes of carrageenan with some drugs (emepronium, doxicicline and propranolol) and with antidepressant drugs have been proposed to reduce the risks of overdosing the drug (WO 93/07860, 1993).
An ofloxacin-carrageenan complex has also been proposed to prepare sustained release tablets, whose release was completed in 2-3 hours (JP 61 130239, 1986). In the methods of complex preparation described in the literature at least one of the interacting species is present in solution; in some cases polymer solutions concentrated at 5% w/v are used (JP 60 174729).
However, in the preparation of solid oral dosage forms (tablets, pills, capsules, granulates), no particular attention has been given, until now, to the particle size of the complex, and quite often high amounts of other excipients have been used to obtain coherent tablets or to slow down the release rate.
Controlled release tablets have many advantages from the technological point of view and for the patient compliance. A thorough formulation study is however necessary to obtain the desired release rate and profile also taking into account the characteristics, for example the pH, of the dissolution medium. When high dosages of a freely soluble drug are needed, this task is rendered more difficult since the quantity of polymers and other excipients to be added to modulate the release must be limited, in order to avoid the preparation of tablets of big dimensions.
The need was felt to have controlled release therapeutical compositions not containing high amounts of polymers and excipients and therefore being of acceptable dimensions for the oral administration.
The present invention relates to a complex of carrageenan with a water soluble drug in powder form with an average particle size ranging from 10 to 100xcexc and the basic water soluble drug is contained in the complex in amounts ranging from 1.5 and 5 mmol/g carrageenan.
The Applicant has in fact surprisingly found that by using the carrageenan complex with the average particle size in the above mentioned range it is possible to prepare controlled release pharmaceutical compositions not suffering from the drawbacks of the above mentioned known controlled release pharmaceutical compositions containing the carrageenan complex.
In fact by using the carrageenan complex according to the present invention it is possible to prepare controlled release pharmaceutical compositions without the need to add high quantities of further excipients or polymers able to further slow down the drug release.
The present invention therefore further relates to controlled release pharmaceutical compositions containing the complex according to the present invention.
The invention also concerns a process for preparing the complex, based on the interaction between polymer and drug when a minimum amount of water is added, therefore unlikely the known processes above reported, it does not require a previous dissolution of the carrageenan and/or the drug in water.
In particular this process according to the present invention comprises the following steps:
a) preparing a homogeneous mixture of drug and carrageenan in suitable quantities in order to obtain a final carrageenan complex wherein the drug is contained amounts comprised between 1.5 and 5 mmol/g carrageenan
b) kneading the mixture in a suitable apparatus by adding a water content expressed as weight ratio water/polymer+water soluble basic substance comprised between 1:3 and 3:1
c) optionally washing the product coming from step (b);
d) drying the mixture.
e) milling the dried product until reaching the desired particle size.
The advantages of the process according to the present invention which does not require a previous solubilization step can be summarised as follows:
the recovery of the complex is much easier than in the prior art processes using high volumes of solvent;
process times are decidedly shorter;
the centrifugation or filtration step of highly viscous carrageenan solution to recover the desired complex is no longer strictly necessary.